Paralog Studies Augment Gene Discovery: DDX and DHX Genes.

TitleParalog Studies Augment Gene Discovery: DDX and DHX Genes.
Publication TypeJournal Article
Year of Publication2019
AuthorsPaine, I, Posey, JE, Grochowski, CM, Jhangiani, SN, Rosenheck, S, Kleyner, R, Marmorale, T, Yoon, M, Wang, K, Robison, R, Cappuccio, G, Pinelli, M, Magli, A, Akdemir, ZCoban, Hui, J, Yeung, WLan, K Y Wong, B, Ortega, L, Bekheirnia, MReza, Bierhals, T, Hempel, M, Johannsen, J, Santer, R, Aktas, D, Alikaşifoğlu, M, Bozdogan, S, Aydin, H, Karaca, E, Bayram, Y, Ityel, H, Dorschner, M, White, JJ, Wilichowski, E, Wortmann, SB, Casella, EB, Kitajima, JPaulo, Kok, F, Monteiro, F, Muzny, DM, Bamshad, M, Gibbs, RA, V Sutton, R, Van Esch, H, Brunetti-Pierri, N, Hildebrandt, F, Brautbar, A, Van den Veyver, IB, Glass, I, Lessel, D, Lyon, GJ, Lupski, JR
Corporate AuthorsUniversity of Washington Center for Mendelian Genomics, Baylor-Hopkins Center for Mendelian Genomics, Telethon Undiagnosed Diseases Program
JournalAm J Hum Genet
Date Published2019 Aug 01
KeywordsDEAD-box RNA Helicases, Exome Sequencing, Female, Genetic Association Studies, Humans, Infant, Infant, Newborn, Male, Mutation, Missense, Neoplasm Proteins, Neurodevelopmental Disorders, Pedigree, RNA Helicases

Members of a paralogous gene family in which variation in one gene is known to cause disease are eight times more likely to also be associated with human disease. Recent studies have elucidated DHX30 and DDX3X as genes for which pathogenic variant alleles are involved in neurodevelopmental disorders. We hypothesized that variants in paralogous genes encoding members of the DExD/H-box RNA helicase superfamily might also underlie developmental delay and/or intellectual disability (DD and/or ID) disease phenotypes. Here we describe 15 unrelated individuals who have DD and/or ID, central nervous system (CNS) dysfunction, vertebral anomalies, and dysmorphic features and were found to have probably damaging variants in DExD/H-box RNA helicase genes. In addition, these individuals exhibit a variety of other tissue and organ system involvement including ocular, outer ear, hearing, cardiac, and kidney tissues. Five individuals with homozygous (one), compound-heterozygous (two), or de novo (two) missense variants in DHX37 were identified by exome sequencing. We identified ten total individuals with missense variants in three other DDX/DHX paralogs: DHX16 (four individuals), DDX54 (three individuals), and DHX34 (three individuals). Most identified variants are rare, predicted to be damaging, and occur at conserved amino acid residues. Taken together, these 15 individuals implicate the DExD/H-box helicases in both dominantly and recessively inherited neurodevelopmental phenotypes and highlight the potential for more than one disease mechanism underlying these disorders.

Alternate JournalAm J Hum Genet
PubMed ID31256877
PubMed Central IDPMC6698803
Grant ListUM1 HG006542 / HG / NHGRI NIH HHS / United States
R35 NS105078 / NS / NINDS NIH HHS / United States
K08 HG008986 / HG / NHGRI NIH HHS / United States
R01 DK078121 / DK / NIDDK NIH HHS / United States
K12 DK083014 / DK / NIDDK NIH HHS / United States
UM1 HG006493 / HG / NHGRI NIH HHS / United States
T32 GM008307 / GM / NIGMS NIH HHS / United States

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